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Hypertension and the Cortisol-Cortisone Shuttle

Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom

Address all correspondence and requests for reprints to: Paul M. Stewart, M.D., F.R.C.P., F.Med.Sci., Professor of Medicine, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk.

11ß-Hydroxysteroid dehydrogenase type 2 (11ß-HSD2) plays a crucial role in converting hormonally active cortisol to inactive cortisone, thereby conferring specificity on the mineralocorticoid receptor. Mutations in the gene encoding 11ß-HSD2 (HSD11B2) account for an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess, in which cortisol induces hypertension and hypokalemia. A similar clinical picture to apparent mineralocorticoid excess occurs after the ingestion of licorice and carbenoxolone, which are competitive inhibitors of 11ß-HSD2. Reduced 11ß-HSD2 activity may explain the increased sodium retention in preeclampsia, renal disease, and liver cirrhosis. Substrate saturation of 11ß-HSD2 occurs in Cushing’s syndrome and explains the mineralocorticoid excess state that characterizes ectopic ACTH syndrome. Polymorphic variability in the HSD11B2 gene in part determines salt sensitivity, a forerunner for adult onset hypertension. Furthermore, reduced placental 11ß-HSD2 expression might underpin the Barker hypothesis, the epidemiological link between reduced birth weight and adult hypertension. At a prereceptor level, 11ß-HSD2 plays a key role in normal physiology in the corticosteroid regulation of sodium homeostasis and pathophysiology of hypertension.

This work was supported by a Deutsche Forschungsgemeinschaft postdoctoral research fellowship grant (QU142/1-1, to M.Q.) and the Medical Research Council (senior clinical fellowship, to P.M.S.).

Abbreviations: AME, Apparent mineralocorticoid excess; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; icv, intracerebroventricular; MR, mineralocorticoid receptor; THE, tetrahydrocortisone; THF, 5ß-tetrahydrocortisol; UFE, urinary free cortisone; UFF, urinary free cortisol.

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